Empagliflozin slows down natural kidney senescence via Six1/Wnt4/NF-κB pathway.

Age-related renal impairment often occurs insidiously and has become an important cause of chronic renal failure, especially when individuals with other chronic diseases. However, there is lack of effective treatments. Research on diabetic patients has revealed that empagliflozin (EMPA), one of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, exhibits a distinct protective effect on aging kidneys. EMPA has been shown to improve renal fibrosis and ameliorate inflammatory cytokines, including IL-1 and IL-8, which are closely associated with the aging process in db/db mouse models. As a result, we assessed markers indicative of kidney senescence P16 and senescence-associated β-galactosidase (SA-β-gal) in the renal tissue of male C57 mice undergoing natural aging, following treatment with EMPA. Our findings showed that in Old-EMPA group, the expression of P16 and SA-β-gal were downregulated compared to Old-vehicle group, while these markers were expressed lower in Young group. RNA sequencing analysis indicated that our findings correlated with increased expressions of Six1 and Wnt4 in the kidney. Protein-protein interaction (PPI) analysis confirmed an interaction between Six1 and Wnt4. After treatment with EMPA, the expression of Six1 and Wnt4 was observed to increase in both aging Primary renal tubular epithelial cells (PRTECs) and HK-2 cells, whereas the expression of NF-κB and its downstream effectors IL-1β and TNF-α decreased, leading to an improvement in aging-related changes.